Ischemia-induced norepinephrine release, but not norepinephrine-derived free radicals, contributes to myocardial ischemia-reperfusion injury.
ABSTRACT Norepinephrine (NE)-derived free radicals may contribute to myocyte injury after ischemia -reperfusion, so the influence of sympathetic denervation on myocardial ischemia - reperfusion injury was investigated in the present study.
Cardiac sympathetic denervation was produced in Wistar rats by a solution of 10% phenol 1 week before ischemia. Atenolol (0.5 mg/kg) was intravenously administered 10 min before the coronary occlusion. The left coronary artery was occluded for 30 min and thereafter reperfused. Cardiac interstitial fluid was collected by a microdialysis probe and free radicals in dialysate were determined by electron paramagnetic resonance (EPR) spin trapping, using 5,5-dimethyl-1-pyrroline-N-oxide as a spin trap. The ratio of infarct size to the ischemic area at risk (I/R) was decreased in both the phenol and atenolol groups compared with control (28.5+/-11.3, 31.8+/-10.7 vs 50.6+/-14.7%, p<0.05). During the coronary occlusion, concentrations of interstitial NE increased markedly in the control and atenolol groups, but was unchanged in the phenol group. EPR signal intensity (relative value to internal standard) was maximal at 1 h after reperfusion and was similar in the phenol and control groups (0.32+/-0.15 vs 0.45+/-0.19).
Cardiac denervation protected myocyte against ischemia-reperfusion injury through decreasing direct NE toxicity, but not through decreasing NE-derived free radicals.
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ABSTRACT: Background Ischemic preconditioning (IPC) produces immediate tolerance to subsequent prolonged ischemia/reperfusion (I/R), although the underlying mechanism remains unknown. The purpose of this study was to examine the role of nitric oxide (NO) and protein kinase C (PKC) in IPC-attenuated post ischemic leukocyte-endothelium interactions. Methods and Results Male Sprague-Dawley rats were randomized (n=8 per group) into 5 groups: sham-operated control group, IPC group, I/R group (4 h of pubic epigastric artery ischemia followed by 2 h of reperfusion), IPC+I/R group (30 min of ischemia followed by 30 min of reperfusion before I/R), and chelerythrine (PKC inhibitor) +IPC +I/R group. Intravital microscopy was used to observe leukocyte-endothelium interaction and to quantify functional capillaries in rat cremaster muscle flaps. The mRNA expressions of neuronal (n) NO synthase (NOS), inducible (i) NOS, and endothelial (e) NOS were determined by reverse transcription-polymerase chain reaction. The results showed that besides increasing functional capillary density, IPC also prevents I/R-induced increases in leukocyte rolling, adhesion, and migration. In the chelerythrine+IPC+I/R group, the IPC protective action was inhibited by the addition of chelerythrine. It was also observed that IPC upregulated nNOS, iNOS, and eNOS mRNA in I/R injured tissue, but this effect was not blocked by chelerythrine. Furthermore, specifically pretreated nNOS and iNOS inhibitors, along with a nonselective NOS inhibitor, were used in the IPC +I/R group to examine their possible antagonistic effects on leukocyte-endothelium interactions. Inhibition of the nNOS and iNOS activities did not block the beneficial effects of IPC. In contrast, pretreatment with the nonselective NOS inhibitor (NG-nitro-L-arginine methylester) in the IPC+I/R group almost completely blocked the protective effect of IPC. Conclusions Both NOS and PKC play a protective role during IPC, but probably in distinct ways. Furthermore, the results also indicate that eNOS, but not nNOS nor iNOS, is the key mediator of IPC-attenuated I/R-induced microcirculatory disturbance.Circulation Journal 08/2006; 70(8):1070-1075. DOI:10.1253/circj.70.1070 · 3.69 Impact Factor
Circulation Journal 01/2006; 70(11):1509-1514. DOI:10.1253/circj.70.1509 · 3.69 Impact Factor
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ABSTRACT: Endogenous catecholamines released during myocardial ischemia have been considered both to aggravate cell injury and exacerbate arrhythmias and to exert a protective action on the post-ischemic contractile function. The present work was addressed to look for evidence to explain this controversy. The effects of cardiac catecholamine depletion and of alpha- and beta-adrenoceptor (AR) blockade on the post-ischemic contractile dysfunction, as well as its possible relationship with cardiac oxidative stress, were studied in isolated and perfused rat hearts submitted to 20 min of ischemia and 30 min of reperfusion (stunning). Catecholamine depletion improves the contractile recovery in the stunned heart. This mechanical effect was associated with decreased levels of lipid peroxidation. A similar enhancement of the contractile function during reperfusion was detected after the simultaneous blockade of alpha 1- and beta-ARs with prazosin plus propranolol. To ascertain which specific AR pathway was involved in the effects of catecholamines on the stunned heart, selective AR blockers, prazosin (alpha 1-blocker), atenolol (beta 1-blocker), ICI 118,551 (beta 2-blocker) and selective inhibitors of Gi-PI3K pathway (pertussis toxin and wortmannin) were alternatively combined. The results indicate that catecholamines released during ischemia exert a dual action on the contractile behavior of the stunned heart: a deleterious effect, related to the activation of the beta 2-AR-Gi-PI3K-pathway, which was counteracted by a beneficial effect, triggered by the stimulation of alpha 1-AR. Neither the depression nor the enhancement of the post-ischemic contractile recovery were related with the increase in ROS formation induced by endogenous catecholamines.Archiv für Experimentelle Pathologie und Pharmakologie 05/2006; 373(1):60-70. DOI:10.1007/s00210-006-0045-6 · 2.36 Impact Factor